Funding opportunities

Enhancing Survival of Embryonic Stem Cell-Derived Grafts by Induction of Immunological Tolerance

Funding Type: 
New Faculty I
Grant Number: 
Principle Investigator: 
Funds requested: 
$1 581 056
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
SYNOPSIS: This is an application for support to reduce the need for antigen-matched ESCs for therapeutic purposes by developing strategies to induce tolerance to the engrafted cells. The PI will use a mouse model, no human ES cells are proposed for this work. It is a global project that starts with undifferentiated mouse ES cells that will be differentiated into hematopoietic stem cells both to induce tolerance in the bone marrow, and to “cure” type I diabetes in a mouse model by alleviating the destruction of pancreatic cells by the immune system. The hypothesis being tested is that establishing central and peripheral immune tolerance will reduce the need for antigen-matched donor ES cells. The investigator’s career development plan is aspirational and is aimed to have educational support benefits for other staff. The host institution is clearly highly supportive of the applicant and has major long term plans in the fields of regenerative medicine and bioengineering. STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: This is a well written application from a young faculty member that addresses a central issue in the utility of hESCs in human therapy and overcoming the challenge of patient immune response to hESC therapies. Tumorigenicity and immunological intolerance of ES cells are a bit over-stated in the application, but the research plan as a whole is well-designed, potential problems addressed, and may yield useful results in this mouse model. The experimental design appears to be appropriate as it develops on existing expertise with supportive preliminary data, although there does not appear to be an evaluation of the difficulty of developing the pancreatic stem cell lines to be used. The staff appear to provide strong and trained support and timelines seem generally realistic although the investigator may wish to consider the possibility of aim 1 taking a full 2 years. Three specific aims are proposed: Aim 1 will establish an optimal protocol for differentiation and engraftment of ESC-derived hematopoietic precursors (ES-HP) in adult mice. Aim 2 will determine whether immunological tolerance is achieved in mice receiving allogeneic ES-HP and define the mechanisms underlying tolerance induction. Aim 3 will validate that ES-HP co-transplantation can enhance survival of ES-derived tissue grafts and cure recipients that suffer from degenerative disease. Although the “cure” of Type I diabetes by bone marrow engraftment is not universally accepted by all experts in the field, the work proposed in this application will yield valuable information about the role of tolerance in ES cell therapies. QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: Dr. Manilay is an assistant professor at the School of Natural Sciences, University of California, Merced. She received a BA in Molecular and Cell Biology from UC Berkeley in 1992, followed by a PhD in Immunology from Harvard University and a five –year post-doc at UC Berkeley in developmental immunology. She joined the faculty at UC Merced in 2005. UC Merced is a new UC campus, beginning in the fall of 2005. Thus, Dr. Manilay is a founding faculty member. She has 13 peer-reviewed publications, all in the areas of immune cell biology, including transplanted immune cells. The career plan is truly aspirational with local mentors of excellent quality. However, there is not a clear and formal mechanism by which mentor feedback will be achieved. Her career plan involves both teaching and research, particularly in immune stem cell biology. Her enthusiasm for her career goals is evident from her descriptions of milestones. INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: University of California, Merced, is a new institution within the UC system. Dr. Manilay is clearly a founding member of stem cell biology at UC Merced. A letter of support from the Dean of Natural Sciences emphasizes a commitment to Dr. Manilay's research efforts, including increased protected time for research commensurate with research funding. The host institution is very supportive providing various central facilities and there is evidence of ongoing commitment to expanding the developmental biology and bioengineering areas. She is in the new Science and Engineering building, completed in 2006. Facilities and equipment for this project appear to be in place. DISCUSSION: Reviewers express reservation, that although the applicant has had excellent training, her overall accomplishments and publications have not been particularly outstanding thus far. Additionally, the research proposal is problematic. The proposed project is an ambitious one that intends to go from mouse ESCs to hematopoietic cells to curing diabetes. The entire proposal hinges on the success of the first aim and reviewers expressed concern that the project may not work. Hematopoietic reconstitution in the proposal is unclear; she wants to induce tolerance to cells so they have to persist in some way. Reviewers expressed enthusiasm for this young investigator and agreed that this is a well-trained scientist with enormous support from the host institution. The applicant has an aspirational and commendable career development plan that includes both research and teaching. However, enthusiasm for the applicant and the institutional support could not overcome the concerns with the scientific proposal.

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